Description: Three eminent scientists in biology and medical engineering discuss their pioneering work at MIT -- a research base they regard as unmatched for its collaborative environment and enthusiasm for even the most marginal and offbeat ideas. Moderator and colleague Hazel Sive hails these speakers as among those who have helped "move women to where they should be as intellectual leaders."

Susan Lindquist explains her investigation of a unicellular organism -- yeast -- leading to an understanding of "some of mankind's most devastating diseases," including ALS, Parkinson's, Huntington's, and dementia. All these neurodegenerative disorders are characterized by "globs of misfolded proteins" such as the amyloid plaques seen in Alzheimer's patients.

Lindquist notes that long strings of amino acids are powerless until they assume intricate shapes to code DNA. This occurs in "an absolutely ridiculous environment," she remarks. "Not only is it crowded, but the cells are experiencing a tremendous amount of kinetic energyconstantly bumping into each othernot like Fred Astaire and Ginger Rogersmore like the characters in a Marx Brothers movie where chaos is poised on the precipice of disaster." Neurons are especially prone to detrimental outcomes of protein misfolding, more so with age.

Yeast serves as Lindquist's experimental subject because it is cheap, fast growing, easily manipulated, and sports a thoroughly documented genome, making it "a living test tubea dream come true for biology." Through genetic screens, she identifies compounds that ultimately can be applied therapeutically in humans. The goal is to treat Parkinsonism via "personalized medicine" according to the unique genetic composition of a given patient in order to obtain optimal response.

JoAnne Stubbe speaks passionately about radicals, "reductive metabolites of oxygen gas." Commonly thought of as destructive, these mercurial molecules cause oxidation that may mutate DNA, and in turn, result in disease or aging. Conversely, they can also exhibit beneficial behavior. "Nature has figured out how to harness the reactivity of these radicals to do extremely challenging chemistry with exquisite specificity," says Stubbe.

In particular, Stubbe's work concentrates on ribonucleotide reductases (RNRs), enzymes crucial to DNA replication and repair via a catalytic reaction with free radicals. Her laboratory has been unraveling this process for over 30 years. She calls ribonucleotide reductases "a veritable playground for free radical chemistry." Her efforts have proven fruitful not only in theoretical discovery but also in therapeutic applications. RNRs are targets of clinical drugs for leukemia and other hematological cancers.

Stubbe concludes by broadening the scope "for those of you who like to think about evolution." RNRs are essential intermediaries in the polypeptide assembly machine, the process by which proteins are synthesized. These radical"exploiting enzymes are integral to the creation of every life form by enabling the transformative link from RNA to DNA.

Sangeeta Bhatia explores signaling pathways, structures, and functional interdependencies within tissue microenvironments of 100 microns and smaller. "Five hundred to 50 nanometersis the perfect length scale" for examining the microenvironment of the liver, in which hepatocytes are her interest.

Because liver failure is lethal and donor organs are scarce, Bhatia hopes to build "an engineered liver that you would implant off the shelf." Since the liver conducts 500 functions, this is a daunting mission requiring versatile cell architecture, chemistry and proliferation. Conventional CAD manufacturing methods can construct infinitesimal 3D scaffolding that suspends cross"linked cells in a liquid "like fruits in Jell"O," Bhatia says. Thus far, she and her team have made minuscule disk"shaped livers for mice. "We need about 10 billion cells to get into a human patient," she declares with determination.

Bhatia also studies the detoxification capability of the liver, and is developing drugs to fight infections. Currently she has a pharmaceutical compound in clinical trials for hepatitis C. She exclaims, "This was a real thrill as an inventor." In addition, she is pursuing the malaria"inducing parasite that initially attacks hepatocytes before bursting into the bloodstream.

About the Speaker(s): Hazel Sive is Associate Dean of the School of Science at MIT as well as Professor of Biology and Member of the Whitehead Institute for Biomedical Research. She arrived at Whitehead in 1991, where her work focuses on zebrafish and frog embryos to understand the evolution and molecular structure of the vertebrate nervous system.

In 1992, Sive was named a Searle Scholar and received a National Science Foundation Young Investigator Award. Sive earned her undergraduate degree from the University of
Witwatersrand in Johannesburg, South Africa, in chemistry
and zoology and her Ph.D. from Rockefeller University in molecular biology, in 1986.

Sive traces the earliest stages of neural development in vertebrates. She has identified more than 50 genes involved in the decision to begin making neural tissue from the undifferentiated cells in a young embryo. The work could provide new insights into neurological diseases, spinal cord injuries, and cancer.

Host(s): Office of the President, MIT150 Inventional Wisdom

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